Aberrant or excessive activity or dysregulation of activity of receptor protein tyrosine kinase (RPTK) has been observed in many disease states including benign and malignant proliferative disorders as well as inflammatory disorders and immune system disorders that result from inappropriate activation of the immune system to cause, for example, autoimmune diseases. So far, there are about 58 kinds of receptor tyrosine kinases, including VEGF receptors, PDGF receptor (PDGF receptor (PDGFR) family is composed of five kinds of RTK composition: PDGFR-a and -b, c-kit and FLT3), and flk receptor family and so on. These receptors can transduce signals to other tyrosine kinases, such as Src, Raf, Frk, Btk, Csk, Abl, Fes/Fps, Fak, Jak, Ack, etc.
FLT3 plays an important role in the proliferation and differentiation of hematopoietic stem cells, and activating mutation or overexpression of this receptor is found in AML (acute myeloid leukemia) (See, Heinrich, Mini-Reviews in Medicinal Chemistry, 2004, 4(3): 255-271, and Kiyoi et al., Int J Hematol., 2005, 82: 85-92, incorporated herein by reference). One study shows the FLT3 inhibtor CEP-701 may be effective in reducing myelin loss in experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis (See, Whartenby et al., PNAS, 2005, 102: 16741-16746, incorporated herein by reference). A high level of the FLT3 ligand is found in the serum of patients with Langerhans cell histiocytosis and systemic lupus erythematosus, that further means FLT3 signal transduction is implicated in the dysregulation of dendritic cell progenitors in those autoimmune diseases (See, Rolland et al., J. Immunol., 2005, 174:3067-3071, incorporated herein by reference).
Activating internal tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) are detected in approximately 20% of acute myeloid leukemia patients and are associated with a poor prognosis. Research has shown that FLT3-ITD can represent a driver lesion, which has causative role in malignancy pathogenesis, and valid therapeutic target in human AML (See, Catherine et al., Nature, 2012, 485: 260-263, incorporated herein by reference). Mutation of FLT3 gene is a frequent event in AML and usually involves internal tandem duplication (ITD) of the juxtamembrane domain coding region or point mutations of the tyrosine kinase domain (TKD). Both FLT3-ITD and FLT3-TKD mutations result in ligand-independent proliferation due to constitutive dimerisation and activation of the FLT3 receptor. High mutant-to-wild type allelic ratios of FLT3-ITD are associated with a very poor prognosis in both adults and children (See, A S Moore et al., Leukemia, 2012, 26: 1462-1470, incorporated herein by reference).
bcr-Abl is a tyrosine kinase which inhibits cellular cancerization and immortalization of pH-positive chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). bcr-Abl protein is the constitutively active, cytoplasmic tyrosine kinase existing in 90% of the patients of chronic myeloid leukemia and 15-30% of the adult patients of acute lymphoblastic leukemia. Many studies have shown that bcr-Abl activation is the need of carcinogenic ability of said chimeric protein.
In recent years, the abnormalities of c-Kit gene, a member of type III receptor tyrosine kinase family in AML, have attracted more attentions. It was found that mutations of c-KIT gene will cause the activation of c-Kit without receptor-ligand binding, thereby the abnormal proliferation of cells occurs, leading to cancer. c-KIT gene mutation in leukemia cell is closely associated with the occurrence of leukemia and the prognosis of therapeutic agent. c-Kit receptor also can be constitutively activated by mutation, leading to abnormal cell proliferation and development, such as mastocytosis (D816V mutation) and other diseases, and various cancers, such as GIST (c-kitΔ27, juxtamembrane deletion).